TY - JOUR
T1 - Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability As a Biomarker in Gastric Cancer
AU - Pietrantonio, Filippo
AU - Miceli, Rosalba
AU - Raimondi, Alessandra
AU - Kim, Young Woo
AU - Kang, Won Ki
AU - Langley, Ruth E.
AU - Choi, Yoon Young
AU - Kim, Kyoung-Mee
AU - Nankivell, Matthew Guy
AU - Morano, Federica
AU - Wotherspoon, Andrew
AU - Valeri, Nicola
AU - Kook, Myeong-Cherl
AU - An, Ji Yeong
AU - Grabsch, Heike I.
AU - Fuca, Giovanni
AU - Noh, Sung Hoon
AU - Sohn, Tae Sung
AU - Kim, Sung
AU - Di Bartolomeo, Maria
AU - Cunningham, David
AU - Lee, Jeeyun
AU - Cheong, Jae-Ho
AU - Smyth, Elizabeth Catherine
N1 - Funding Information:
There was no specific funding source for this work. ECS thanks the Cambridge Biomedical Research Center for their support. RMH authors acknowledge the support of the NIHR RM/ICR BRC. Translational work on the MAGIC trial was supported by Cancer Research UK Grant C20023/ A7217. Work on ITACA-S was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), work on ARTIST and CLASSIC was supported by the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea.
Funding Information:
There was no specific funding source for this work. ECS thanks the Cambridge Biomedical Research Center for their support. RMH authors acknowledge the support of the NIHR RM/ICR BRC. Translational work on the MAGIC trial was supported by Cancer Research UK Grant C20023/ A7217. Work on ITACA-S was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), work on ARTIST and CLASSIC was supported by the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea. We thank all of the patients who participated in the included studies.
Funding Information:
1Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2University of Milan, Milan, Italy 3National Cancer Center, Goyang, Korea 4Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea 5The Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom 6Yonsei University College of Medicine, Seoul, Korea 7Royal Marsden Hospital, London and Sutton, United Kingdom 8The Institute of Cancer Research, London, United Kingdom 9GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands 10Leeds Institute for Medical Research at St James’s, University of Leeds, Leeds, United Kingdom 11Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Publisher Copyright:
Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
PY - 2019/12/10
Y1 - 2019/12/10
N2 - PURPOSE In the CLASSIC and MAGIC trials, microsatellite instability (MSI)-high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value.PATIENTS AND METHODS We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery v surgery) with MSI.RESULTS MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio [HR], 1.88; 95% CI, 1.28 to 2.76; P <.001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73; P = .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12).CONCLUSION In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.
AB - PURPOSE In the CLASSIC and MAGIC trials, microsatellite instability (MSI)-high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value.PATIENTS AND METHODS We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery v surgery) with MSI.RESULTS MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio [HR], 1.88; 95% CI, 1.28 to 2.76; P <.001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73; P = .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12).CONCLUSION In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.
KW - MISMATCH REPAIR
KW - PERIOPERATIVE CHEMOTHERAPY
KW - ADJUVANT CHEMOTHERAPY
KW - DOUBLE-BLIND
KW - ADENOCARCINOMA
KW - CAPECITABINE
KW - GUIDELINES
KW - CISPLATIN
KW - SURVIVAL
KW - THERAPY
KW - Adenocarcinoma
KW - Therapy
KW - Adjuvant chemotherapy
KW - Capecitabine
KW - Double-blind
KW - Survival
KW - Cisplatin
KW - Guidelines
KW - Mismatch repair
KW - Perioperative chemotherapy
U2 - 10.1200/JCO.19.01124
DO - 10.1200/JCO.19.01124
M3 - Article
SN - 0732-183X
VL - 37
SP - 3392
EP - 3400
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 35
ER -